Tato stránka byla automaticky přeložena a přesnost překladu není zaručena. Podívejte se prosím na anglická verze pro zdrojový text.

An Efficacy and Safety Study of Fixed-dose Rosiglitazone/Glimepiride to Treat Chinese Type 2 Diabetes Patients

22. března 2012 aktualizováno: GlaxoSmithKline

A Multi-center, Randomized, Double-blind, Parallel-group Study to Compare the Efficacy and Safety of Fixed-dose Rosiglitazone/Glimepiride Combination Therapy With Glimepiride Monotherapy for 24 Weeks in Drug Naive Subjects With Type 2 Diabetes

The purpose of this study is to demonstrate that the rosiglitazone/glimepiride fixed-dose combination tablet will safely and effectively control glycemia as first-line oral therapy in drug naïve subjects with type 2 diabetes. This 24-week study will compare the effects of treatment with rosiglitazone/glimepiride to treatment with glimepiride alone. The primary objective is to demonstrate superiority of rosiglitazone/glimepiride to glimepiride in lowering Glycosylated Hemoglobin (HbA1c).

Přehled studie

Postavení

Ukončeno

Podmínky

Intervence / Léčba

Detailní popis

The antihyperglycemic effect of the thiazolidinedione (TZD) class of oral antidiabetic agents is due to their ability to increase insulin sensitivity at the cellular level, which in turn improves the ability of endogenous insulin to regulate glucose utilization by the tissues. Compounds of the sulfonylurea (SU) class act to stimulate insulin production by the pancreas, overcoming insulin resistance by increasing circulating insulin levels. The mechanisms of two kind OADs may be viewed as complementary, offering the opportunity for improved efficacy and durability of effect through coadministration of a TZD and a sulfonylurea.

Successful management of type 2 diabetes mellitus (T2DM) requires aggressive glycemic control starting at the earliest stages of the disease. Rosiglitazone/glimepiride combination therapy, with complementary mechanisms of action, has the potential to provide significant benefits over monotherapy as first line therapy. Treatment with rosiglitazone/glimepiride at this early stage of diabetes is expected to provide better glycemic control and allow a greater proportion of patients to achieve target glycemic goals than oral monotherapy.

This was a multicenter, randomized, double-blinded, parallel, study to compare the effects of treatment with rosiglitazone/glimepiride combination or glimepiride in drug naïve T2 DM patients.

Typ studie

Intervenční

Zápis (Aktuální)

86

Fáze

  • Fáze 3

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní místa

  • Čína
      • Beijing, Čína, 100029
        • GSK Investigational Site
      • Beijing, Čína, 100730
        • GSK Investigational Site
      • Chongqing, Čína, 400016
        • GSK Investigational Site
      • Shanghai, Čína, 200080
        • GSK Investigational Site
      • Shenyang, Čína, 110003
        • GSK Investigational Site
      • Tianjin, Čína, 300052
        • GSK Investigational Site
      • Wuhan, Čína, 430022
        • GSK Investigational Site
    • Hubei
      • Wuhan, Hubei, Čína, 430030
        • GSK Investigational Site
    • Jiangsu
      • Suzhou, Jiangsu, Čína, 215004
        • GSK Investigational Site
    • Liaoning
      • Dalian, Liaoning, Čína, 116027
        • GSK Investigational Site
    • Zhejiang
      • Hangzhou, Zhejiang, Čína, 310009
        • GSK Investigational Site
      • Hangzhou, Zhejiang, Čína, 310003
        • GSK Investigational Site

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

18 let až 75 let (Dospělý, Starší dospělý)

Přijímá zdravé dobrovolníky

Ne

Pohlaví způsobilá ke studiu

Všechno

Popis

Inclusion Criteria:

  • type 2 diabetes mellitus
  • HbA1c between 7.5% and 11.0% at screening
  • FPG between 7.0mmol/L and 13.3mmol/L at screening and at randomization visit
  • subject was treated with diet and/or exercise alone
  • QTc<450mesc or QTc<480msec for patients with bundle branch block
  • Body Mass Index (BMI) >19kg/m2
  • Subject has given written informed consent

Exclusion Criteria:

  • Documented history of significant hypersensitivity to thiazolidinediones, sulfonylureas, or compounds with similar chemical structures
  • Ongoing edema or history of edema requiring pharmacological treatment in the 12 months prior to screening
  • Presence of ischemic heart disease and/or peripheral arterial disease, or NYHA grade I-IV congestive heart failure
  • Taking nitrates
  • Clinically significant renal or hepatic disease
  • Anemia
  • Severe hypertriglyceridemia (TG>=5.65mmol/L)
  • Use of oral corticosteroids and Nicotinic acid
  • Systolic blood pressure <170mmHg, or diastolic blood pressure > 100mmHg while on anti-hypertensive treatment
  • Hyperthyroidism requiring treatment
  • Diagnosed macular edema
  • Women who are lactating, pregnant, or planning to become pregnant
  • Presence of an active cancer or recently treated for cancer
  • Drug/alcohol abuse
  • Unwilling or unable to comply with the procedures described in the protocol

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: Randomizované
  • Intervenční model: Paralelní přiřazení
  • Maskování: Dvojnásobek

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Experimentální: fix dose of rosiglitazone/glimepiride
4mg/1mg, 4mg/2mg, 4mg/4mg
Lék: rosiglitazone/glimepiride fix dose combination
oral, once daily, dosage is titrated according to FPG and hypoglycemia events
Ostatní jména:
  • Avandaryl
Aktivní komparátor: glimepiride
1mg, 2mg, 4mg
Lék: glimepiride
oral, once daily, dosage is titrated according to FPG and hypoglycemia
Ostatní jména:
  • Amaryl

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
Časové okno: Baseline (Week 0) and Week 24
Blood samples of participants were collected for HbA1c assessment. HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over a 2- to 3-month period. The American Diabetes Association has recommended an HbA1c value below 53 millimoles per mole (mmol/mol) (7.0%) for most participants. Change from Baseline in HbA1c was calculated as the value at Week 24 minus the value at Baseline.
Baseline (Week 0) and Week 24

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Časové okno: Baseline (Week 0) and Week 24
Blood samples of participants were collected for FPG assessment. The FPG test, also known as the fasting blood sugar test, measures blood sugar levels after the participant has not eaten (fasted) for 12 to 14 hours. Change from Baseline in FBG was calculated as the value at Week 24 minus the value at Baseline.
Baseline (Week 0) and Week 24
Number of HbA1c Responders and Non-responders
Časové okno: Baseline (Week 0) and Week 24 (LOCF)
Blood samples of participants were collected for HbA1c assessment. HbA1c responders were defined as participants who had achieved HbA1c <7%, or who achieved a decrease of >= 0.7% from Baseline at Week 24 (LOCF).
Baseline (Week 0) and Week 24 (LOCF)
Number of FPG Responders and Non-responders
Časové okno: Baseline (Week 0) and Week 24 (LOCF)
Blood samples of participants were collected for FPG assessment. FPG responders are definded as participants who had a >=1.7 mmol/L decrease from Baseline FPG or who achieved a FPG level < 6.1 mmol/L at Week 24 (LOCF).
Baseline (Week 0) and Week 24 (LOCF)
Number of Participants Who Achieved HbA1c <7%, HbA1c <=6.5%, or Who Achieved a Decrease of >=0.7% From Baseline
Časové okno: Baseline (Week 0) and Week 24 (LOCF)
Blood samples of participants were collected for HbA1c assessment.
Baseline (Week 0) and Week 24 (LOCF)
Change From Baseline in Fasting Proinsulin and Insulin at Week 24/Early Withdrawal (EW)
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants who had fasted for 12-14 hours were collected for fasting proinsulin (precursor of insulin) and insulin assessment. Preproinsulin is sequentially processed via proinsulin, through intermediate proteolytic cleavage products, to insulin and C-peptide before release from the beta cell granule by exocytosis. Elevated levels of proinsulin are considered indicative of beta cell dysfunction. Insulin is a hormone that regulates carbohydrate and fat metabolism in the body. Change from Baseline was calculated as the value at Week 24/ EW minus the value at Baseline (Week 0).
Baseline (Week 0) and Week 24/EW
Change From Baseline in Homeostasis Model Assessment Sensitivity (HOMA-S) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants who had fasted for 12-14 hours were collected for fasting glucose (FG) and insulin (FI) assessment. The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance (a condition in which natural hormone insulin becomes less effective in lowering blood sugars) and beta-cell (specialized cells in the pancreas producing insulin) function. HOMA-S is calculated using the following model to predict glucose and insulin concentrations=(FI[milliunits (mU)/milliliter (ml)]*FG [millimoles per liter (mmol/l)])/22.5. numerator, num.; denominator, denom.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Homeostasis Model Assessment Beta-cell Function (HOMA-B) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants who had fasted for 12 to 14 hours were collected for fasting glucose (FG) and insulin (FI) assessment. The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance (a condition in which natural hormone insulin becomes less effective in lowering blood sugars) and beta-cell (specialized cells in the pancreas producing insulin) function. HOMA-B is calculated using the following mathematical model to predict glucose and insulin concentrations=(20*FI[mU/ml])/(FG[mmol/l]-3.5).
Baseline (Week 0) and Week 24/EW
Number of Participants at Various Dose Levels at Week 24/EW
Časové okno: Week 24/EW
The number of participants at the different dose levels at Week 24/EW was recorded. The different dose levels for Rosi + Glim are: Dose level 1, Rosi 4 mg + Glim 1 mg; Dose level 2, Rosi 4 mg + Glim 2 mg; Dose level 3, Rosi 4 mg + Glim 4 mg. The different dose levels for Glim are: Dose level 1, Glim 1 mg; Dose level 2, Glim 2 mg; Dose level 3, Glim 4 mg.
Week 24/EW
Change From Baseline in Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C), Low Density Lipoprotein-cholesterol (LDL-C), and Triglyceride (TG) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants who had fasted for 12 to 14 hours were collected for lipid profile (TC, HDL-C, LDL-C, TG) assessment. The lipid profile asesses the risk of heart disease. Change from Baseline in TC, HDL-C, LDL-C, and TG was calculated as the value at Week 24)/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Blood Urea Nitrogen (BUN), Sodium, Potassium, Chloride, Calcium, and Phosphorus at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for BUN and electrolyte (sodium, potassium, chloride, calcium, and phosphorus) assessment. The electrolyte balance asseses the condition of the heart and the kidneys, and BUN assesses the condition of the kidneys. Change from Baseline in BUN, sodium, potassium, chloride, calcium, and phosphorus was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in the Ratio of TC/HDL-C and LDL-C/HDL-C at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants who had fasted for 12 to 14 hours were collected for lipid profile (TC, HDL-C and LDL-C) assessment. The ratio of TC/HDL-C and LDL-C/HDL-C was calculated. Change from Baseline in the ratio of TC/HDL-C and LDL-C/HDL-C was calculated as the value at Week 24/EW minus the value at Baseline. For TC/HDL-C, the numerator is TC, and the denominator is HDL-C. For LDL-C/HDL-C, the numerator is LDL-C, and the denominator is HDL-C.
Baseline (Week 0) and Week 24/EW
Change From Baseline in High Sensitivity C-reactive Protein (Hs-CRP) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for hs-CRP assessment. CRP is a marker of inflammation. High levels of CRP predict the risk of heart disease and diabetes. Change from Baseline in hs-CRP was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Percent Change From Baseline in High Sensitivity C-reactive Protein (Hs-CRP) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for hs-CRP assessment. CRP is a marker of inflammation. High levels of CRP predict the risk of heart disease and diabetes. Percent change from Baseline in hs-CRP was calculated as the value at Visit 8 (Wk 24)/ EW minus the value at Baseline divided by value at Wk 24/ EW multiplied by 100.
Baseline (Week 0) and Week 24/EW
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
EQ-5D is used as a measure of health outcome and includes single-item measures (coded on a 3-point scale [1, no problems; 2, some problems; 3, severe problems]) of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The instrument includes a global rating of current health using a visual analog scale (VAS): 0 (worst imaginable) to 100 (best imaginable). Health states may be converted to a single summary index by applying a formula that attaches values to each of the levels in each dimension. The index scale is -0.111 to 1. A lower index indicates worse health.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Adjusted Diabetes Quality of Life (A-DQOL) Scores at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
In diabetic participants, QOL, anxiety, and depression were measured by the A-DQOL scale . There are 46 core items (10 additional items for adolescents) and 4 major dimensions: treatment satisfaction, treatment impact, worry about long-term complications, and worry about social/vocational issues. Participants respond to all items on a 5-point Likert scale: 1, no impact, no worries, or always satisfied; 5, always affected, always worried, or never satisfied. The total score is a sum of the individual scores of all 46 items (range of 46 to 230); a lower score indicates a better QOL.
Baseline (Week 0) and Week 24/EW
Number of Participants With Hypoglycemic Events
Časové okno: Week 24/EW
Blood samples of participants were collected for the assessment of blood glucose levels. Hypoglycemia is a condition that occurs when the blood glucose is below 70 mg/dL or 4 mmol/L. All participants; participants with HbA1c <7%, or who achieved a decrease of >= 0.7% from Baseline at Week 24 (HbA1c responders); and participants who had a >=1.7 mmol/L decrease from Baseline FPG or who achieved a FPG <6.1 mmol/L at Week 24 (FPG responders) were evaluated.
Week 24/EW
Number of Hypoglycemic Events
Časové okno: Week 24/EW
A hypoglycemic event is a condition that occurs when the blood glucose is below 70 mg/dL or 4 mmol/L. All participants, participants with HbA1c <7%, or who achieved a decrease of >= 0.7% from Baseline at Week 24 (HbA1c responders); and participants who had a >=1.7 mmol/L decrease from Baseline FPG or who achieved a FPG <6.1 mmol/L at Week 24 (FPG responders) were evaluated.
Week 24/EW
Number of Participants With a Bone Fracture
Časové okno: Week 24/EW
Participants with a break in the continuity (fracture) of the bone were evaluated.
Week 24/EW
Change From Baseline in White Blood Cell (WBC) Count and Platelet Count at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for WBC count and platelet count assessment. Change from Baseline in WBC count and platelet count was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Red Blood Cell (RBC) Count at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for RBC count assessment. Change from Baseline in RBC count was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Lymphocytes, Monocytes, Neutrophils, Eosinophils, and Basophils at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for lymphocyte, monocyte, neutrophil, eosinophil, and basophil assessment. Change from Baseline in lymphocytes, monocytes, neutrophils, eosinophils, and basophils was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Hematocrit (HCT) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for HCT assessment. Change from Baseline in HCT was calculated as the value at Week 24/EW minus the value at Baseline. HCT is measured as the percentage of the volume of whole blood that is made up of red blood cells.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Hemoglobin (HE), Mean Corpuscular Hemoglobin Concentration (MCHC), Total Protein (TP), and Albumin at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for HE, MCHC, and TP assessment. Change from Baseline in HE, MCHC, and TP was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Mean Corpuscular Volume (MCV) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for MCV assessment. Change from Baseline in MCV was calculated as the value at Week 24/EW minus the value at Baseline. MCV is the average size of the red blood cells expressed in femtoliters. MCV is calculated by dividing the hematocrit (as percent) by the RBC count in millions per microliter of blood, then multiplying by 10. MCV is one of the three main RBC indices that are helpful in determining the cause of anemia.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Mean Corpuscular Hemoglobin (MCH) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for MCH assessment. Change from Baseline in MCH was calculated as the value at Week 24/EW minus the value at Baseline. MCH is the average amount of hemoblobin inside a RBC expressed in picograms. MCH is calculated by dividing the hemoglobin concentration in grams per deciliter by the RBC count in millions per microliter, then multiplying by 10. MCH is one of the three main RBC indices which are helpful to determine the cause of anemia.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Alanine Transaminase (ALT), Aspartate Aminotransferase (AST), Gamma-glutamyl Transpeptidase (GGT), Lactate Dehydrogenase (LDH), Alkaline Phosphatase (ALP), and Creatine Kinase (CK) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for ALT, AST, GGT, LDH, ALP, and CK assessment. Change from Baseline in ALT, AST, GGT, LDH, ALP, and CK was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Total Bilirubin (TB), Direct Bilirubin (DB), Creatinine, and Uric Acid (UC) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Blood samples of participants were collected for TB, DB, creatinine, and UC assessment. Change from Baseline in TB, DB, creatinine, and UC was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
The blood pressure of the participants was measured. Change from Baseline in SBP and DBP was calculated as the value at Weeks 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Heart Rate at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
The heart rate of the participants was measured. Change from Baseline in heart rate was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Weight at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
The weight of the participants was measured. Change from Baseline in weight was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Electrocardiogram (ECG) Assessment of Heart Rate at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
Electrocardiograms of the participants were taken for the evaluation of heart rate. Change from Baseline in heart rate was calculated as the value at Week 24/EW minus the value at Baseline.
Baseline (Week 0) and Week 24/EW
Change From Baseline in Electrocardiogram (ECG) Data at Week 24/EW
Časové okno: Baseline (Week 0) and Week 24/EW
PR, QT, QTc, RR, QRS, and QRS axis data were measured by ECG. The PR interval (int.) starts at the beginning of the atrial contraction and ends at the beginning of the ventricular contraction. QT (QT int.) and QTc (corrected QT int.) indicate how fast the ventricles are repolarized, becoming ready for a new cycle. The RR int. represents the duration of the ventricular cardiac cycle and is an indicator of ventricular rate. QRS (QRS duration) indicates how fast the ventricles depolarize. The QRS axis is an indicator of the electrical heart axis, which is an average of all heart depolarization.
Baseline (Week 0) and Week 24/EW

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

GlaxoSmithKline

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia

1. dubna 2010

Primární dokončení (Aktuální)

1. října 2010

Dokončení studie (Aktuální)

1. října 2010

Termíny zápisu do studia

První předloženo

13. října 2011

První předloženo, které splnilo kritéria kontroly kvality

13. října 2011

První zveřejněno (Odhad)

17. října 2011

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Odhad)

27. března 2012

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

22. března 2012

Naposledy ověřeno

1. prosince 2011

Více informací

Termíny související s touto studií

Klíčová slova

Další relevantní podmínky MeSH

Další identifikační čísla studie

  • 113263

Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .

Klinické studie na Diabetes mellitus, typ 2

Klinické studie na rosiglitazone/glimepiride fix dose combination

Prohledejte podobné pokusy

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

CROs by country

CROs in Czech Republic

Podmínky

Vzácné nemoci

Drogové intervence

Doplňky stravy

Sponzor / Spolupracovníci

Místa

3
Předplatit